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William M. Wason, MD, PhD Confusion Abounds 9/24/2010 Rheumatoid arthritis: ulnar deviation and muscle artrophy, hands • Poor sensitivity and specificity • Hepatitis C causes lots of “false +” tests • Changing technology in how tests are done – Historic data based on immunofluorescent testing g – 125 different antigens ‐ ANA – Current testing based largely on ELISA test tube technology – 10 antigens • No absolute standardization between labs • Values can vary from week‐to‐week even in the same lab with the same patient Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Serologic Testing should Ideally be used to Confirm a Diagnosis, not “Shotgun” a Problematic Patient Testing for RA • Diagnosis of RA still remains a clinical diagnosis – Symmetrical inflammatory arthritis affecting large and small joints lasting 6 weeks or longer • Lab tests that are helpful – Rheumatoid Factor – Anti‐CCP antibody – ESR, CRP The Ideal Lab Test Rheumatoid factors (diagram) • True positive: Sick people correctly diagnosed as sick (sensitivity 100%) • True negative: Healthy people correctly identified as healthy (specificity 100%) Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. William M. Wason, MD, PhD 9/24/2010 Rheumatoid factor in rheumatic disease Rheumatoid arthritis Systemic lupus erythematosus Sjögren's syndrome Systemic sclerosis Dermatomyositis/polymyositis Vasculitis Cryoglobulinemia Juvenile rheumatoid arthritis Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Rheumatoid factor in nonrheumatic diseases Normal individuals (< 5%) Elderly Bacterial infections Endocarditis Leprosy Syphilis Lyme disease Periodontal disease Viral infections Hepatitis C (also A & B) Parvovirus Rubella CMV HIV EBV Anti‐CCP Antibody (CCP) Anti‐cyclic citrullinated protein Parasitic diseases Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Rheumatoid factor in nonrheumatic diseases, cont’d Anti‐CCP Lymphoproliferative disease Interstitial lung disease Chronic liver disease Sarcoidosis • Positive test has 94% certainty patient has RA • Negative does not R/O RA Post-vaccination Malignancies • Strongly positive test associated with more severe disease • Test may become positive a few years before disease becomes apparent Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. William M. Wason, MD, PhD 9/24/2010 Anti‐Nuclear Antibodies (ANA) • Immunofluorescent test on HEP‐2 cells – 125 different antigens detected – Positive titers reported: 1:40 to 1:1280 Lab Testing for RA Principle of indirect immunofluorescence (diagram) • Rheumatoid Factor has lots of “False +” and lots of “False –” tests • CCP has very few has very few “False False ++” • ESR and CRP are useful in determining severity of disease activity Copyright © 1972‐2004 American College of Rheumatology Slide Collection. All rights reserved. Systemic lupus erythematosus: malar rash, face Antinuclear antibodies (photomicrographs) Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved. William M. Wason, MD, PhD 9/24/2010 Immunofluorescent Testing – – – – – – – Homogenous Diffuse Peripheral Rim Speckled Nucleolar Anti‐centromere, etc. • Subject to operator interpretation • Labor intensive • Most literature based on this methodology ELISA Most commonly used today Highly reproducible Automated M hl Much less likely to interpretation bias lik l t i t t ti bi Misses many minor ANAs found on immunofluorescent testing • Most literature based on older immunofluorescent method • • • • • Anti‐Nuclear Antibodies (ANA) • ELISA solid phase immunoassay – Usually limited to 8‐10 antigens – Usually >100 are considered positive Usually >100 are considered positive Principles of enzyme‐linked immunosorbent assay (diagram) Common ANA sub‐types ‐ ELISA • • • • • SS – DNA DS – DNA Anti‐Smith Anti‐Histone Anti‐RNP • • • • • SSA (Ro) SSB (La) Scl‐70 Anti‐Centromere JO‐1 Antibody ANA with Reflex testing (ELISA) • Screening test to mixture of all antigens • Negative – no further testing • Positive – Will do specific testing to all antigens – By design, if you get a positive screen, you will get a B d i if t iti ill t positive sub‐type antigen – Cost depends on Negative/Positive result • ?Best Test Copyright © 1972‐2004 American College of Rheumatology Slide Collection. All rights reserved. – Screen with ELISA – Confirm with IF at >1:40 titer – Sub‐type with ELISA William M. Wason, MD, PhD 9/24/2010 Other Labs • CBC • Chem Profile • Urine Analysis • Spot Urine Protein/Creatinine Ratio • Uric Acid (gout) • CPK (inflammatory muscle disease) • ESR >50 • Hepatitis C • False + tests, Cryoglobulinemia, Arthritis, Vasculitis • Hepatitis B • Reactivation with immunosuppression, PAN • CXR • Interstitial Lung Disease, Occult Malignancy, Sarcoidosis, Rheumatoid Nodules, Baseline for Drug Tx. Random Protein/Creatinine Ratio • Technique: Random urine collection – Calculate Urine Protein mg to Urine Creatinine mg Ratio • Interpretation of Urine Protein to Urine Creatinine Ratio – Adults and children over age 2 years • Normal ratio <0.2 grams protein per gram Creatinine – Correlates with 0.2 g protein/day • Nephrotic Ratio >3.5 (correlates with 3.5 g protein) • References – Ruggenenti (1998) BMJ 316:504 – (2002) Am J Kidney Dis 39:S1 Summary Hepatitis C • Negative ANA, generally excludes • Patients with Hep C infections have false positive tests for virtually all rheumatology l b labs – SLE – Drug induced SLE – MCTD • Positive ANA, has only a 20% probability of being associated with significant CVD associated with significant CVD • Low titer ANA rarely associated with significant CVD – CCP antibody appears to be the only exception • Positive CCP antibody, generally confirms RA • Patients need to be cautioned these tests are not fool‐ proof and must be interpreted with the clinical circumstances